Division of Gastroenterology and Hepatology, Shanghai Jiao-Tong University School of Medicine Renji Hospital, Shanghai, China.
J Lipid Res. 2013 Jan;54(1):44-54. doi: 10.1194/jlr.M026013. Epub 2012 Oct 15.
Our objective was to investigate the potential roles of CCN1 in the inflammation and macrophage infiltration of nonalcoholic fatty liver disease (NAFLD). The regulation of hepatic CCN1 expression was investigated in vitro with murine primary hepatocytes treated with free fatty acids or lipopolysaccharide (LPS) and in vivo with high-fat (HF) diet-fed mice or ob/ob mice. CCN1 protein and a liver-specific CCN1 expression plasmid were administered to mice fed a normal diet (ND) or HF diet. Myeloid-derived macrophages and RAW264.7 cells were also treated with CCN1 in vitro to determine the chemotactic effects of CCN1 on macrophages. LPS treatment significantly increased hepatic CCN1 expression in HF diet-fed mice and ob/ob mice. LPS and FFAs induced CCN1 expression in primary murine hepatocytes in vitro through the TLR4/MyD88/AP-1 pathway. CCN1 protein and overexpression of CCN1 in the liver induced more severe hepatic inflammation and macrophage infiltrates in HF mice than in ND mice. CCN1 recruited macrophages through activation of the Mek/Erk signaling pathway in myeloid-derived macrophages and RAW264.7 cells in vitro. Endotoxin and FFA-induced CCN1 expression in hepatocytes is involved in the hepatic proinflammatory response and macrophage infiltration in murine NAFLD.
我们的目的是研究 CCN1 在非酒精性脂肪性肝病 (NAFLD) 炎症和巨噬细胞浸润中的潜在作用。通过用游离脂肪酸或脂多糖 (LPS) 处理的原代鼠肝细胞和高脂肪 (HF) 饮食喂养的小鼠或 ob/ob 小鼠体内研究肝 CCN1 表达的调节。CCN1 蛋白和肝特异性 CCN1 表达质粒被给予正常饮食 (ND) 或 HF 饮食喂养的小鼠。体外还对髓样来源的巨噬细胞和 RAW264.7 细胞进行 CCN1 处理，以确定 CCN1 对巨噬细胞的趋化作用。LPS 处理显著增加了 HF 饮食喂养的小鼠和 ob/ob 小鼠肝脏中 CCN1 的表达。LPS 和 FFAs 通过 TLR4/MyD88/AP-1 通路诱导原代鼠肝细胞中 CCN1 的表达。CCN1 蛋白和肝内 CCN1 的过表达在 HF 小鼠中引起比 ND 小鼠更严重的肝炎症和巨噬细胞浸润。CCN1 通过髓样来源的巨噬细胞和 RAW264.7 细胞中 Mek/Erk 信号通路的激活募集巨噬细胞。肝内细胞因子和 FFA 诱导的 CCN1 表达参与了鼠 NAFLD 中的肝前炎症反应和巨噬细胞浸润。
